FDA Grants Orphan Drug Designation to MB-106 for Waldenström Macroglobulinemia


The FDA has granted an orphan drug designation to the CD20-targeted autologous CAR T-cell therapy, MB-106, for use as a potential therapeutic option in patients with Waldenström macroglobulinemia.

The FDA has granted an orphan drug designation to the CD20-targeted autologous CAR T-cell therapy, MB-106, for use as a potential therapeutic option in patients with Waldenström macroglobulinemia.1

The product was developed by Brian Till, MD, an associate professor in the Clinical Research Division at Fred Hutch and was licensed in 2017 to Mustang Bio.

CD20 is a membrane-embedded surface molecule that has been proven to be an effective therapeutic target in B-cell non-Hodgkin lymphoma (B-NHL), as evidenced by previously approved anti-CD20 antibodies and encouraging efficacy observed with bispecific antibodies.2 MB-106 is a fully human, third-generation, CD20-targeted CAR T-cell therapy with 4-1BB and CD28 costimulatory domains.

The safety and efficacy of the CAR T-cell therapy is under evaluation in patients with high-risk B-NHLs, as part of a phase 1/2 trial (NCT03277729). Data from a cohort of patients with follicular lymphoma that were presented during the 2022 EHA Congress demonstrated that the agent had favorable efficacy and safety in this population.2

In this cohort, MB-106 resulted in an objective response rate (ORR) of 94% (n = 17/18), with a complete response (CR) rate of 78% (n = 14), and a partial response (PR) rate of 17% (n = 3). One patient experienced disease progression. In the 2 patients with Waldenström macroglobulinemia, the ORR achieved with the agent was 100%, with a CR rate of 100%.

“We are pleased to receive orphan drug designation from the FDA, as it is an important regulatory milestone for Mustang’s MB-106 program for the treatment of Waldenström macroglobulinemia, a rare B-NHL with a significant unmet medical need,” Manuel Litchman, MD, president and chief executive officer of Mustang Bio, stated in a press release.

To be eligible for participation on the single-institution, phase 1/2 trial examining MB-106, patients needed to have CD20-positive B-NHL. If they had follicular lymphoma, they were required to have previously received at least 1 line of treatment.

Those with large cell lymphoma (LBCL) needed to have received 2 prior lines of therapy; those with mantle cell lymphoma (MCL) needed to receive at least 1 prior line of treatment with a BTK inhibitor; and those with chronic lymphocytic leukemia (CLL) were required to have received a prior BTK inhibitor and/or have experienced venetoclax (Venclexta) failure in the form of disease progression or intolerance.

Previous treatment with a CD19-targeted CAR T-cell therapy was permitted following the recovery of normal B cells.

First, patients were screened, and tumor biopsies were done; this was followed by leukapheresis and the subsequent production of the CAR T-cell therapy, which took approximately 10 days to complete. Patients then underwent lymphodepletion with a chemotherapy regimen comprised of cyclophosphamide and fludarabine.

Thirty-six to 96 hours later, patients underwent infusion with the CAR T-cell therapy at the following dose levels: 1 x 105 cells/kg (dose level 0), 3.3 x 105 cells/kg (dose level 1), 1 x 106 cells/kg (dose level 2), 3.3 x 106 cells/kg (dose level 3), and 1 x 107 cells/kg (dose level 4). Treatment was administered in the outpatient setting, except for the first patient treated on each dose level. Seven to 16 days after infusion, another tumor biopsy was done.

The original cell manufacturing process that had been used for the trial from 2017 to 2019 required separate culturing of CD4- and CD8-positive cells and lymphodepletion regimens that could have consisted of cytarabine alone or in combination with fludarabine. Using this process, 7 patients were treated and experienced stable disease (SD) as their best response to treatment. Due to challenges with meeting target cell doses, poor CAR T expansion, and a lack of clinical responses, a hold was placed on enrollment and the process was revised.

The modified process, which combines culture of CD4- and CD8-positive cells, was initiated in 2019. As of June 6, 2022, a total of 26 patients reached the day-28 assessment for safety and efficacy. At the congress, investigators shared data on patients with follicular lymphoma who received treatment with MB-106 through the modified process (n = 18).

Among 28 patients enrolled to this cohort, the median age was 61.8 years (range, 44.7-81.3), with 25% of patients older than 65 years and 7% older than 80 years. Slightly more than half of patients (55.5%) were female, and the majority had stage III/IV disease at initial diagnosis (89%) and histologic grade 1 or 2 disease at diagnosis (61%).

The median number of prior lines of therapy received was 5, with a range of 1 to 12. Seventeen percent of patients had a history of transformation, 67% experienced progressive disease within 24 months of frontline chemoimmunotherapy, and 5.5% previously received a CD19-targeted CAR T-cell therapy.

Additional data showed that in the 2 patients with MCL, the ORR was 100% with the CAR T-cell therapy, and all patients experienced PRs with treatment. In the 2 patients with CLL, the ORR was 100% with MB-106, which comprised a 50% CR rate and a 50% PR rate. Lastly, in those with diffuse large B-cell lymphoma (DLBCL; n = 2), the ORR was 100%, with both patients achieving complete responses.

Regarding safety, 27.5% of the 18 evaluable patients with follicular lymphoma experienced cytokine release syndrome with MB-106 in the first 28 days; this was grade 1 in 22% of patients and grade 2 in 5.5% of patients. No patients experienced immune effector cell–associated neurotoxicity syndrome with the CAR T-cell therapy.

Other adverse effects reported with the agent included lymphopenia (100%), neutropenia (94%), anemia (61%), thrombocytopenia (28%), febrile neutropenia (16.5%), skin infections (5.5%), bacteremia (5.5%), pneumonia (5.5%), and cytomegalovirus (CMV) reactivation (5.5%).

The most common grade 3 effects were lymphopenia (11%), neutropenia (33%), anemia (39%), febrile neutropenia (11%), bacteremia (5.5%), and CMV reactivation (5.5%). Grade 4 lymphopenia was reported in 16 patients, grade 4 neutropenia occurred in 11 patients, and grade 4 thrombocytopenia was observed in 2 patients.

The study continues to enroll patients with CLL, Waldenström macroglobulinemia, DLBCL, and central nervous system lymphoma.


  1. Mustang Bio announces orphan drug designation granted to MB-106, a CD20-targeted, autologous CAR T cell therapy for the treatment of Waldenstrom macroglobulinemia. News release. Mustang Bio, Inc. June 22, 2022. Accessed June 22, 2022. https://bit.ly/3tSKTwY
  2. Shadman M, Yeung C, Redman M, et al. Efficacy and safety of a third generation CD20 CART (MB-106) for treatment of relapsed/refractory follicular lymphoma (FL). Presented at: 2022 EHA Congress; June 9-12, 2022. Abstract S207. https://bit.ly/3neAtUE

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